細川 勇

膵癌は浸潤・転移をきたしやすく悪性度の高い代表的な悪性腫瘍であり,多くの治療に抵抗性を示す。その大きな要因として膵癌細胞を取り巻く微小環境があり,これまで盛んに基礎研究が行われてきている。膵癌微小環境内にはさまざまな癌進展機構にかかわる因子が内包され,膵癌細胞とそれらの因子の相互作用による癌進展機構のメカニズムが解明されつつある。重要な構成成分として成長因子やサイトカインなどの液性因子,癌関連線維芽細胞(CAFs),pancreatic stellate cells(PSCs),癌関連免疫担当細胞があり,また細胞外基質(ECM)を含む豊富な間質を有することが特徴である。現在はそれらを治療ターゲットとした臨床試験が行われており,今後の有望な膵癌新規治療の出現が期待されている。(著者抄録)

BACKGROUND: Although some clinical trials have demonstrated the benefits of neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDAC), its optimal candidate has not been clarified. This study aimed to detect predictive prognostic factors for resectable PDAC patients who underwent upfront surgery and identify patient cohorts with long-term survival without neoadjuvant therapy. PATIENTS AND METHODS: A total of 232 patients with resectable PDAC who underwent upfront surgery between January 2008 and December 2019 were evaluated. RESULTS: The median overall survival (OS) time and 5-year OS rate of resectable PDAC with upfront surgery was 31.5 months and 33.3%, respectively. Multivariate analyses identified tumor diameter in computed tomography (CT) ≤ 19 mm [hazard ratio (HR) 0.40, p < 0.001], span-1 within the normal range (HR 0.54, p = 0.023), prognostic nutritional index (PNI) ≥ 44.31 (HR 0.51, p < 0.001), and lymphocyte-to-monocyte ratio (LMR) ≥ 3.79 (HR 0.51, p < 0.001) as prognostic factors that influence favorable prognoses after upfront surgery. According to the prognostic prediction model based on these four factors, patients with four favorable prognostic factors had a better prognosis with a 5-year OS rate of 82.4% compared to others (p < 0.001). These patients had a high R0 resection rate and a low frequency of tumor recurrence after upfront surgery. CONCLUSIONS: We identified patients with long-term survival after upfront surgery by prognostic prediction model consisting of tumor diameter in CT, span-1, PNI, and LMR. Evaluation of anatomical, biological, nutritional, and inflammatory factors may be valuable to introduce an optimal treatment strategy for resectable PDAC.

BACKGROUND: The relationship between the course of the segment 4 hepatic artery and proximal ductal margin status in the right hepatectomy (H15678-B) for perihilar cholangiocarcinoma is unclear. This study aimed to evaluate proximal ductal margin status according to the course of the segment 4 hepatic artery in patients with perihilar cholangiocarcinoma treated with right hepatectomy. METHODS: Consecutive patients with perihilar cholangiocarcinoma who underwent a right hepatectomy between January 2006 and August 2021 were retrospectively reviewed. The course of the segment 4 hepatic artery was classified based on the positional relationship with the umbilical portion of the left portal vein into R-UP and L-UP types. The R-UP type had the segment 4 hepatic artery running along the right caudal position of the umbilical portion of the left portal vein, whereas the L-UP type had the segment 4 hepatic artery running along the left cranial position of the umbilical portion of the left portal vein, with or without another branch running along the right caudal position of the umbilical portion of the left portal vein. Proximal ductal margin status after the right hepatectomy was compared between types. RESULTS: Among 102 patients, 72 (70.5%) were R-UP type, and 30 (29.5%) were L-UP type. Rates of negative proximal ductal margin were higher with the L-UP type (27/30, 90.0%) than with the R-UP type (51/72, 70.8%; P = .04). On multivariate analysis, Bismuth-Corlette type II and IIIa (risk ratio 4.13, 95% confidence interval 1.52-11.5; P = .005) and L-UP type (risk ratio 4.03, 95% confidence interval 1.18-18.8; P = .04) were independent predictors of negative proximal ductal margin after a right hepatectomy for perihilar cholangiocarcinoma. CONCLUSION: For the course of the segment 4 hepatic artery, L-UP type rather than R-UP type might be anatomically advantageous for achieving negative proximal ductal margin in a right hepatectomy for perihilar cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer. Cases when found are often advanced with vascular invasion, and radical resection is often difficult. Despite curative resection, the postoperative recurrence rate of patients with histological lymph node metastasis is high, and their prognosis is poor. Therefore, there is an urgent need to establish multidisciplinary treatment that combines chemotherapy and surgical resection. The efficacy of neoadjuvant chemotherapy (NAC) for locally advanced ICC is unclear. In this report, a case of locally advanced ICC in which pathological complete response (pCR) was achieved after NAC is described. CASE PRESENTATION: A 79-year-old woman was admitted to a local hospital with appetite loss. Computed tomography showed a 100 × 90 mm low-contrast tumor in the left hepatic lobe and segment 1 with invasion to the inferior vena cava (IVC), and several lymph nodes along the left gastric artery and lesser curvature were enlarged. Therefore, she was treated with a combined chemotherapy regimen of gemcitabine and cisplatin. After four courses, the tumor size decreased to 30 × 60 mm without invasion to the IVC. Left hepatectomy extending to segment 1 with bile duct resection combined with middle hepatic vein resection (H1234-B-MHV), dissection of regional lymph nodes and pyloroplasty were performed. After radical resection, pCR was achieved. She is alive with no evidence of disease, 2 years after surgery. CONCLUSIONS: In this case, a patient with locally advanced ICC achieved pCR to NAC. NAC may be effective for ICC. Patients who achieve pCR may have a better prognosis.

PURPOSE: Systemic chemotherapy is generally used for metastatic pancreatic cancer; however, pulmonary resection may be a treatment option for lung oligometastases from pancreatic cancer. The current study aimed to clarify the oncological outcomes and clinical benefits of pulmonary resection for lung metastases. METHODS: Of 510 patients who underwent pancreatic resection for pancreatic cancer, 44 patients with recurrence of isolated lung metastases and one patient with simultaneous lung metastases were evaluated. RESULTS: Of the 45 patients, 20 patients were selected as candidates for pulmonary resection based on clinical factors such as recurrence-free interval (RFI) from pancreatectomy to lung metastases, number of lung metastases, and serum CA19-9 level. The post-recurrent survival of patients with pulmonary resection was significantly better than that of patients without pulmonary resection. Fourteen of the 20 patients with pulmonary resection developed tumor recurrence with a median disease-free survival (DFS) of 15 months. Univariate analyses revealed that an RFI from pancreatectomy to lung metastases of ≥28 months was associated with better DFS after pulmonary resection. Of the 14 patients with an RFI of ≥28 months, pulmonary resection resulted in prolonged chemotherapy-free interval in 12 patients. Furthermore, repeat pulmonary resection for recurrent tumors after pulmonary resection led to further cancer-free interval in some cases. CONCLUSIONS: Although many patients had tumor recurrence after pulmonary resection, pulmonary resection for lung metastases from pancreatic cancer may provide prolonged cancer-free interval without the need for chemotherapy. Pulmonary resection should be performed for the patients with a long RFI from pancreatectomy to lung metastases.

BACKGROUND: The indication for surgical resection of intraductal papillary mucinous neoplasms (IPMNs) is defined by imaging features, such as mural nodules. Although carbohydrate antigen (CA) 19-9 was selected as a parameter for worrisome features, no serum biomarkers were considered when deciding on surgical indications in the latest international consensus guideline. In this study, we assessed whether clinical factors, imaging findings, and serum biomarkers are useful in predicting malignant IPMNs. METHODS: A total of 234 resected IPMN cases in Chiba University Hospital from July 2005 to December 2021 were retrospectively analyzed. RESULTS: Among the 234 patients with resected IPMNs diagnosed by preoperative imaging, 117 were diagnosed with malignant pathologies (high-grade dysplasia and invasive IPMNs) according to the histological classification. In the multivariate analysis, cyst diameter ≥30 mm; p = 0.035), enhancing mural nodules on multidetector computed tomography (≥5 mm; p = 0.018), and high serum elastase-1 (≥230 ng/dl; p = 0.0007) were identified as independent malignant predictors, while CA19-9 was not. Furthermore, based on the receiver operator characteristic curve analyses, elastase-1 was superior to CA19-9 for predicting malignant IPMNs. Additionally, high serum elastase-1 levels (≥230 ng/dl; p = 0.0093) were identified as independent predictors of malignant IPMNs in patients without mural nodules on multidetector computed tomography (MDCT) in multivariate analysis. CONCLUSION: The serum elastase-1 level was found to be a potentially useful biomarker for predicting malignant IPMNs.

A 73-year-old female was diagnosed with gallbladder cancer, but the future liver remnant volume was deemed insufficient for curative resection. Consequently, transileocolic portal vein embolization was performed. During laparotomy, multiple nodules were palpable on the peritoneal surface of the pelvic floor. Subsequently, staging laparoscopy confirmed the pathological diagnosis of adenocarcinoma in the resected nodules, indicating peritoneal dissemination of gall bladder cancer. Due to this peritoneal dissemination, surgical resection was deemed inappropriate, and the patient was initiated on systemic chemotherapy consisting of gemcitabine and cisplatin. Following 22 courses of chemotherapy, contrast-enhanced computed tomography demonstrated no significant changes in the size of the primary tumor or its location relative to the main vessels, although a small metastatic lesion was identified in the gallbladder bed. At the second staging laparoscopy, any nodules suggesting peritoneal dissemination were observed. Based on these findings, we decided to perform curative resection. The surgical procedure involved right hepatectomy plus segment 4a resection, extrahepatic bile duct resection, and hepaticojejunostomy. Pathological examination revealed ypT3bN0M1(HEP), ypStage ⅣB, with the achievement of R0 resection. The patient survived with no recurrences for 40 months after surgery. These results suggest that aggressive therapeutic strategies, including conversion surgery following systemic chemotherapy, may be beneficial for patients initially deemed unresectable due to gallbladder cancer.

Serial pancreatic juice aspiration cytological examination(SPACE)has been reported as a reliable preoperative diagnostic method for early pancreatic cancer, when combined with imaging findings suspecting early pancreatic cancer. Among 259 patients with suspected pancreatic cancer who underwent pancreatic resection at our hospital, SPACE was preoperatively performed in 14 cases(5.4%). Of these 14 cases, final pathological diagnosis was pancreatic cancer in 12 patients (86%), including 5 patients with Stage ⅠA pancreatic cancer(35.7%), all of whom had a mass on preoperative CT or EUS. On the other hand, in the other 2 cases(14.3%), CT/EUS detected no mass but focal pancreatic parenchymal atrophy and main pancreatic duct stenosis which were the imaging findings suspecting very early pancreatic cancer such as cancer in situ. Although preoperative SPACE results of these 2 cases were class Ⅳ, final pathological results of resected specimen were low-grade PanIN in both cases. SPACE was considered useful for preoperative diagnosis of pancreatic cancer in our study, however further study is needed to examine its diagnostic accuracy for early pancreatic cancer which does not appear as a mass in any imaging modality.

R0切除困難な局所進行肝門部領域胆管癌に対して,化学療法を施行し,化学療法が奏効した症例に対して外科切除を行う(conversion surgery)という治療戦略は,安全で有効な可能性がある。しかし,肝門部領域胆管癌をR0切除困難と判断する基準や,化学療法の効果判定基準,化学療法が奏効しR0切除可能となったと判断する基準には一定のものはなく,施設ごとに大きく異なると予想される。また,近年,胆道癌に対する新規レジメンや,新規抗癌剤,分子標的薬が登場したことから,局所進行肝門部領域胆管癌に対するconversion surgeryの安全性と有効性に関しては,引き続き検討していく必要がある。(著者抄録)

BACKGROUND: Although both proximal ductal margin status and lymph node metastasis status influence the survival of patients with perihilar cholangiocarcinoma, the effect of proximal ductal margin status on survival according to lymph node metastasis status is unclear. The aim of this study was, thus, to evaluate the prognostic impact of proximal ductal margin status in perihilar cholangiocarcinoma according to the presence or absence of lymph node metastasis. METHODS: Consecutive patients with perihilar cholangiocarcinoma who underwent major hepatectomy between June 2000 and August 2021 were retrospectively reviewed. Patients with Clavien-Dindo grade V complications were excluded from the analysis. Overall survival was assessed according to the combination of lymph node metastasis and proximal ductal margin status. RESULTS: Of the 230 eligible patients, 128 (56%) were lymph node metastasis negative, and 102 (44%) were lymph node metastasis positive. Overall survival was significantly better in lymph node metastasis negative than lymph node metastasis positive patients (P < .0001). Of the 128 lymph node metastasis-negative patients, 104 (81%) were proximal ductal margin negative, and 24 (19%) were proximal ductal margin positive. In lymph node metastasis-negative patients, overall survival was worse in the proximal ductal margin positive than the proximal ductal margin negative group (P = .01). Of the 102 lymph node metastasis-positive patients, 72 (71%) were proximal ductal margin negative and 30 (29%) were proximal ductal margin positive. In these patients, overall survival was similar between the 2 groups (P = .10). CONCLUSION: In patients with perihilar cholangiocarcinoma, the prognostic impact of proximal ductal margin positivity on survival might differ according to the presence or absence of lymph node metastasis.

肝門部領域胆管癌に対しては,胆管断端と剥離面からなる切除縁が癌陰性の外科切除(R0切除)が唯一,長期生存の期待できる治療法である。肝門部領域胆管癌においては,胆管断端の癌遺残が予後に与える影響は,遺残した癌が浸潤癌か上皮内癌かだけではなく,T因子やN因子によっても異なる可能性があることを十分理解したうえで,R0切除をめざした積極的な外科切除を基軸とした治療を行っていく必要がある。(著者抄録)